Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related death among men in the U.S. Androgen signaling, mediated through the androgen receptor (AR) and its ligands, testosterone and 5α-dihydrotestosterone (DHT), plays a role in prostate tumorigenesis. The AR is a member of the nuclear hormone receptor superfamily. The unbound AR forms a complex with heat-shock proteins (HSPs) in the cytoplasma. Upon binding to ligands, the AR dissociates from the HSPs and translocates into the nucleus, where it binds to the androgen response element (ARE), recruits transcriptional cofactors, and induces transcription. Primary prostate cancer is androgen dependent, and the AR is expressed in prostate cancer cells. Activation of AR mediated through androgens is involved in prostate tumorigenesis, which leads to prostate cancer growth and survival through the activation of targeted gene expression.
Androgen deprivation therapy (ADT) induces significant regression of prostate tumors, which has been a common strategy for treating advanced prostate cancer. However, while ADT initially achieves therapeutic response, it eventually fails in nearly all patients. Consequently, the patients develop castration resistant prostate cancer (CRPC) that is the invariable recurrence of aggressive, lethal prostate cancer in an androgen-depleted setting within two to three years after initiating therapy. Unfortunately, CRPC is incurable to date and almost every patient with metastatic CRPC eventually succumbs to the disease. Despite many different medications that have been developed and applied to patients since then, the fundamental premise behind androgen deprivation has remained almost unchanged. More than 250,000 men die from lethal prostate cancer worldwide each year. Therefore, therapeutic options for the patients are urgently needed. The disclosure is directed to this, as well as other, important ends.